Mesenchymal stem cells (MSCs) are promising candidates for cell-based therapy, mostly owing to their potent immunosuppressive secretome. MSCs were shown to suppress T cells, B cells, natural killer cells and antigen-presenting cells inflammatory responses, making them of particular interest to treat multiple sclerosis (MS). MS, effecting 2.5M people worldwide, is a tragic neurodegenerative disease, mediated by adaptive and innate autoimmune inflammatory responses in the brain and spinal cord. MS initially follows a relapsing- remitting course (RRMS), with majority of patients eventually developing secondary progressive MS (SPMS), characterized by a progressive and irreversible accumulation of central nervous system (CNS) damage, and for which there is no therapy. While MSCs show beneficial effects in MS preclinical and clinical studies, promoted by MSC-secreted neuroprotective and anti-inflammatory factors, this effect is limited by the poor homing of systemically administered MSCs to inflamed brain and spinal cord. Hence, there exists a need to augment the homing and immunosuppressive properties of MSCs to boost their clinical potential for MS therapy. A potential approach to accomplish this is mRNA transfection, which we have recently used to harness systemically administered MSCs as cellular vehicles for targeted delivery of interleukin-10 (IL-10) to sites of local inflammation, resulting in significan suppression of inflammation. In this proposal, we aim to develop an mRNA-guided therapeutic cellular platform to treat RR and SPMS. We hypothesize that mRNA transfection with CNS-specific homing ligands would enable us to target systemically administered MSCs to MS-diseased brain and spinal cord, increasing local levels of MSC-secreted neurotrophic and immunomodulatory soluble factors in the CNS. By simultaneously transfecting MSCs with additional therapeutic cytokines, such as IL-10, IFN- and IL-27, we will use the infused MSCs as vehicles for targeted delivery of multiple therapeutic factors to the inflamed CNS. Via this approach, we aim to achieve synergism between the mRNA-transfected therapeutic factors and the potent immunosuppressive and neuroprotective agents inherently secreted by MSCs. We envision that this approach would enable us to develop a potent cellular platform that would target both innate and adaptive immune responses, potentially providing an effective treatment for RR and SPMS.